Oncostatin M (OSM) is a pleiotropic cytokine produced by many cell types, including neutrophils and tumor-associated macrophages. OSM inhibits the proliferation of breast cancer cells in vitro, and is therefore being evaluated as a potential cancer therapy. Circumstantial evidence in the literature, however, suggests that OSM could promote angiogenesis in a tumor microenvironment. Our data demonstrates that OSM is expressed by tumor-associated neutrophils and by breast cancer epithelial cells, but not by normal breast tissue. In addition, we have shown that OSM potently induces the pro-angiogenic molecule vascular endothelial growth factor (VEGF) from breast cancer cells, and that VEGF produced by OSM-treated breast cancer cells will induce endothelial cell proliferation and stimulate tube formation. Thus, while OSM may cause growth-arrest in breast cancer cells in vitro, no studies have addressed OSM's ability to induce VEGF from breast cancer cells or to induce angiogenesis-dependent breast cancer progression in the more complex in vivo environment. Our objective is to characterize the role of OSM-induced VEGF in angiogenesis and breast cancer progression. We hypothesize that OSM-treated breast cancer cells will stimulate angiogenesis in vitro and in vivo. Furthermore, we predict that OSM will actually promote tumor progression by initiating or enhancing VEGF-dependent angiogenesis, in spite of its growth-inhibitory properties. Results to this end will not only render OSM unsuitable as a potential breast cancer therapy, but will suggest that OSM itself is a valid therapeutic target. To examine the role of OSM in angiogenesis and tumor progression, we propose to: 1) determine the receptor and signaling pathway utilized by OSM to induce VEGF; 2) demonstrate that VEGF produced by OSM-treated breast cancer cells will induce an angiogenic phenotype in cultured endothelial cells; and 3) establish breast cancer cell lines that overexpress OSM to investigate the ability of OSM to stimulate angiogenesis and promote breast carcinoma progression in vivo. This work could provide evidence that OSM is unsuitable as a potential breast cancer therapy, and establish a foundation for the rational design of experimental, OSM-based anti-angiogenic therapeutics.